The overall goal of this Program is to understand the protein synthesis- dependent synaptic modifications that underlie learning and memory. It has been established that activity stimulates protein synthesis, and that some of these proteins are synthesized from mRNA localized at or near the synapse. The investigators recently described a novel mechanism for such experience-driven local translation wherein translationally dormant synaptic mRNA is polyadenylated through the action of the CPEB (cytoplasmic polyadenylation element binding protein). This discovery provides an unprecedented opportunity to study the role of local mRNA translation in synaptic plasticity, and forms the basis for a coherent, integrated, and broadly-based investigation into the regulation of protein synthesis-dependent synaptic plasticity. Project 1 (Richter) includes the characterization of new CPEB isoforms and a novel targeted CPEB knock-out mouse using Cre-loxP technology; and the identification of additional CPEB-regulated mRNAs. Project 2 (Fallon) includes the localization, at the light and EM level, of CPEB in developing an adult brain, and in cultured hippocampal neurons; the characterization of the intracellular signaling pathways leading from synaptic activation to cytoplasmic polyadenylation; and the regulation of the targeting of CPE- containing mRNAs and of CPEB to dendrites. Project 3 (Bear) will characterize a noel form of protein synthesis-dependent synaptic plasticity (DHPG-LTD); use mice lacking CPEB in the consolidation; and characterize the role of local translation and CPEB in experience- dependent regulation of NMDA receptor subunit expression. There will be two cores, one administrative and the second for the production and maintenance of CPEB knock-out mice, which will be used by all the investigators. These should lead to better understanding of the mechanisms of long-term memory formation. The results could provide insights needed to understand diseases that affect learning and memory, and may be useful in designing therapeutic strategies to combat them.